Formulation for use in a method of treatment of pain

ABSTRACT

Formulations, methods of manufacturing, methods of stabilizing, kits, and uses as medicament are provided, for example for the treatment of pain. The formulations can comprise gabapentin optionally combined with at least one non-opioid pain drug in an aqueous carrier. The pharmaceutical formulation can have a pH of about 2.0 to about 10.0. The at least one non-opioid pain drug can be acetaminophen. The components can be included in any amount suitable for purposes of obtaining properties desirable for an injectable infusion, for example an intravenous infusion.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 62/319,526, filed on Apr. 7, 2016 the contents of which areincorporated by reference in their entireties for all purposes.

TECHNICAL FIELD

Embodiments of the disclosure relate generally to formulations andmethods of treating pain and, in particular, formulations comprisinggabapentin or analogues of gamma-aminobutyric acid (GABA), optionallycombined with at least one non-opioid pain drug.

BACKGROUND

Gabapentin, 1-(aminomethyl) cyclohexane acetic acid, is a structuralanalogue of the neurotransmitter gamma-aminobutyric acid. The oralabsorption of gabapentin is dose-dependent due to a saturable L-aminoacid transport mechanism in the intestine. Thus, the oralbioavailability varies inversely with dose. Following a dosing regimenof 900, 1200, 2400, 3600 and 4800 mg/day given in 3 divided doses, thebioavailability of gabapentin is approximately 60%, 47%, 33% and 27%respectively. Plasma concentrations are proportional with dose up to1800 mg daily and then plateau at approximately 3600 mg daily.

Peroral administration of gabapentin to treat pain, for example in acutepost-procedural pain relief, has been documented by various clinicalstudies. However, the peroral route has disadvantages, includinguncertainty for use as pre-procedural medication. For example,gabapentin has a dose dependent extent of bio-availability, and oralabsorption may be impaired because of loss of gastrointestinal functionor restrictions on oral intake. For example, oral administration ofgabapentin yields lower plasma concentrations because of its lowbioavailability.

Accordingly, there is a need for an injectable pharmaceuticalformulation comprising gabapentin or a derivative of gamma-aminobutyricacid for treating pain in general, including but not limited topost-procedural pain.

SUMMARY

In an embodiment, the present disclosure relates to formulationscomprising gabapentin or a derivative of gamma-aminobutyric acid; incertain embodiments, the formulations further comprise at least onenon-opioid pain drug in an aqueous carrier. The pharmaceuticalformulation can have a pH of about 4.0 to about 8.0. In an embodiment,the derivative of gamma-aminobutyric acid is pregabalin. In anotherembodiment, the non-opioid pain drug is acetaminophen.

In other embodiments, the present disclosure provides methods ofmanufacturing a therapeutically effective injectable pharmaceuticalformulation.

In other embodiments, the present disclosure provides methods ofstabilizing a therapeutically effective injectable pharmaceuticalformulation.

In other embodiments, the present disclosure provides kits comprising atleast one dosage form comprising an injectable pharmaceuticalformulation and instructions for administering the at least one dosageform.

In other embodiments, the present disclosure provides uses of gabapentinor a derivative of gamma-aminobutyric acid optionally combined with atleast one non-opioid pain drug for preparation of a medicament to treatpain, wherein the medicament is administered by a dosing regimen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides Table 2 showing the stability of gabapentin in thepresence of different stabilizers and solvents.

FIG. 2 provides Table 10 showing the stability of the acetaminophen andgabapentin formulation at different pH ranges (pH range 4.0-8.0).

FIG. 3 provides a graph showing the results of a tail-flick test: theblack circles (●) represent the vehicle, the square (▪) representsmorphine, the triangle (▴) represents acetaminophen, the invertedtriangle (▾) represents gabapentin, and the diamond (♦) representsacetaminophen and gabapentin combined.

DETAILED DESCRIPTION

The following detailed description is exemplary and explanatory and isintended to provide further explanation of the present disclosuredescribed herein. Other advantages, and novel features will be readilyapparent to those skilled in the art from the following detaileddescription of the present disclosure.

The term “injectable infusion” should be construed to include differentkinds of injectable delivery systems, including parenteral infusion,intravascular infusion, intra-arterial infusion, and intravenousinfusion.

The term “formulation” should be construed to include an injectableinfusion system comprising gabapentin, or a derivative ofgamma-aminobutyric acid optionally combined with at least one non-opioidpain drug, and optionally a buffer, optionally an antioxidant,optionally a preservative, optionally a stabilizing agent, optionally anisotonicity adjusting agent, for parenteral delivery to a subject.

The term “pain” should be construed to include all forms and intensitiesof pain, including but not limited to acute pain, chronic pain,nociceptive pain, inflammatory pain, pathological pain, pre-surgicalpain, surgical pain, post-surgical pain and neuropathic pain.

The term “procedure” should be construed to include different kinds ofoperations, including medical operations and surgical operations.

The term “subject” should be construed to include patients, for examplemedical or surgical patients, and other individuals suffering from pain,for example post-procedural pain.

To overcome the disadvantages of the conventional oral administration ofgabapentin to treat pain, the inventors herein discovered an injectablepharmaceutical formulation comprising gabapentin or a derivative ofgamma-aminobutyric acid optionally combined with at least one non-opioidpain drug for administration. The formulations may be administered atany time, including pre-procedure, peri-procedure, intra-procedureand/or post-procedure for treating pain, including post-procedural pain.As discussed above, there are disadvantages and uncertainties of oralabsorption of gabapentin, including dose-dependent decrease inbioavailability. The inventors have discovered that these disadvantagescan be solved by parenteral route of administration of a pharmaceuticalformulation comprising gabapentin or a derivative of gamma-aminobutyricacid optionally combined with at least one non-opioid pain drug. Thepharmaceutical formulations of the present disclosure can achieveefficient and effective management of pain, including post-proceduralpain. No such formulation is available in the market or reported in theliterature.

Embodiments of the disclosure provide injectable pharmaceuticalformulations and methods. In one embodiment, a formulation per thepresent disclosure comprises gabapentin or a derivative ofgamma-aminobutyric acid optionally combined with at least one non-opioidpain drug in an aqueous carrier. In one embodiment, the derivative ofgamma-aminobutyric acid is pregabalin. The aqueous carrier can be anyaqueous carrier suitable for purposes of obtaining properties desirablefor an injectable infusion, including, for example (without limitation),one or more of water, saline, lactated Ringer's solution, and Ringer'sacetate solution.

In one embodiment, the non-opioid pain drug can be a non-steroidalanti-inflammatory drug. Suitable non-steroidal anti-inflammatory drugsfor use in the present formulations and methods can comprise one or moreof the following: acetaminophen, Aspirin (acetylsalicylic acid),Diflunisal, salicylic acid, salicylates, Salsalate, Ibuprofen,Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen,Flurbiprofen, Oxaprozin, Loxoprofen, indomethacin, Tolmetin, Sulindac,Etodolac, Ketorolac, Diclofenac, Aceclofenac, Nabumetone, Piroxicam,Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam, Phenylbutazone,Mefenamic acid, Meclofenamic acid, Flufenamic acid, Tolfenamic acid,Celecoxib and combinations thereof. In one embodiment, the non-opioidpain drug comprises acetaminophen.

In one embodiment, the pharmaceutical formulation can comprise one ormore of the following: an antioxidant, a buffer, a preservative, astabilizing agent, and an isotonicity adjusting agent. The buffer can beany buffer suitable for purposes of obtaining properties desirable foran injectable infusion, including, for example (without limitation), oneor more of acetic acid, sodium acetate, citric acid, sodium hydroxide,cysteine hydrochloride, sodium dihydrogenphosphate, and disodiumhydrogenphosphate. The buffer can be included in any amount suitable forpurposes of obtaining properties desirable for an injectable infusion,for example in an amount of about 0.1 mM to 200 mM.

In one embodiment, the pharmaceutical formulation can be free frompreservatives. In other embodiments, the pharmaceutical formulation cancomprise one or more preservative agents suitable for purposes ofobtaining properties desirable for an injectable infusion, including,for example (without limitation), one or more of quaternary ammoniumsalts, surfactant and disinfectant agents, for example benzalkoniumchloride, cetremide or cetrimonium chloride or bromide, benzododeciniumbromide, miramine, cetylpyridinium chloride, polidronium chloride orpolyquarternium-1, polyquaternium-42 (also known as polexitonium),sepazonium, etc., mercurial derivatives, for example phenylmercury salts(acetate, borate or nitrate), mercuriothiolate sodium (otherwise calledthiomersal or thimerosal), mercurobutol, amidines, for examplechlorhexidine digluconate or polyhexamethylene biguanide (PHMB),alcohols, for example phenol, thimerosal, benzyl alcohol,phenoxyethanol, chlorobutanol or phenylethanol, phenoxyethanol, andparabens or esters, for example parahydroxybenzoic acid, methylparaben,and propylparaben. In one embodiment, the concentration of thepreservatives is between about 0.001% w/w and less than about 5% w/w ofthe total composition, for example between about 0.003% and about 2.0%w/w of the total formulation.

In one embodiment, the pharmaceutical formulation can comprise one ormore isotonicity agents suitable for purposes of obtaining propertiesdesirable for an injectable infusion, including, for example (withoutlimitation), sodium chloride, glycerol, and thioglycerol.

In one embodiment, the pharmaceutical formulation can comprisepharmaceutically acceptable excipients, for example one or more ofbuffers, preservatives, and antioxidants, and any pharmaceuticallyacceptable mixture thereof.

In one embodiment, the pharmaceutical formulation can be free fromantioxidants. The inventors have unexpectedly discovered thatpharmaceutical formulations according to the present disclosure with noantioxidants, and particularly with no N-acetyl cysteine, have increasedstability.

In other embodiments, the pharmaceutical formulation can comprise one ormore antioxidants suitable for purposes of obtaining propertiesdesirable for an injectable infusion, including, for example (withoutlimitation), one or more of hydrophobic anti-oxidants, for examplebutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, andα-tocopherol, DL-tocopherol, α-tocopherol acetate, TocopherolPolyethylene Glycol Succinate (Vitamin E TPGS), L-cysteine, orhydrophilic anti-oxidants, including sodium EDTA and thioglycerol. Inone embodiment, the concentration of the antioxidants is between 0.005%and 5% w/w of the total formulation. In one embodiment, the one or moreantioxidants can improve the stability of the pharmaceuticalformulation.

In one embodiment, the pharmaceutical formulation according to thepresent disclosure has a pH suitable for purposes of an injectableinfusion. For example, the pH can be about 2.0 to about 10.0, about 4.0and 8.0, or about 6.0 to about 7.0. In one embodiment, one or morebuffer systems are used to stabilize the pH at a desired value or range.Suitable buffers include, for example (without limitation) citric acidbuffer, acetic acid buffer, maleic acid buffer, phosphoric acid buffer,succinic acid buffer, and tartaric acid buffer. The buffer strength canbe any buffer strength suitable for purposes of an injectable infusion,for example (without limitation) between about 0.1 mM to 200 mM.

In one embodiment, administration of the injectable pharmaceuticalformulation according to the present disclosure to a subject occurs atleast one of pre-procedure, peri-procedure, intra-procedure and/orpost-procedure. In one embodiment, administration of the injectablepharmaceutical formulation to a subject is intravascular, for exampleintravenous. In one embodiment, administration of the injectablepharmaceutical formulation is to a subject having pain, including forexample, post-procedural pain. In one embodiment, the pharmaceuticalformulation according to the present disclosure treats post-proceduralpain.

In one embodiment, the pharmaceutical formulation according to thepresent disclosure is packaged in a container. The container can be anycontainer suitable for purposes of injectable infusion, including, forexample (without limitation), a polymer bag, for example an infusionbag, or a glass bottle. In one embodiment, the polymer bag is furtherpackaged in an aluminum over-wrap. In one embodiment, the polymer bag oraluminum over-wrap comprises an oxygen scavenger or an oxygen barrier.In another embodiment, an oxygen scavenger or oxygen barrier is betweenthe polymer bag and the aluminum over-wrap or external to the aluminumover-wrap. In one embodiment, the pharmaceutical formulation accordingto the present disclosure comprises an aqueous solution comprising anoxygen scavenger.

In one embodiment, the polymer bag comprises a dual chamber bag. In thisembodiment, the gabapentin or the derivative of gamma-aminobutyric acidis separated from the at least one non-opioid pain drug. The gabapentinor the derivative of gamma-aminobutyric acid can be separated from theat least one non-opioid pain drug by any suitable barrier. In anotherembodiment, the gabapentin or the derivative of gamma-aminobutyric acidand the non-opioid pain drug are in separate polymer bags, and caneither be mixed in a single container prior to administration, or mixedduring administration, for example by direction of both into a single IVline via a Y-connector.

The term “oxygen scavenger” or “oxygen barrier” should be construed toinclude a substance that consumes, depletes or reduces the amount ofoxygen from a given environment without negatively affecting thepharmaceutical formulation. Suitable oxygen scavenging elements include,for example (without limitation) compositions comprising metalparticulates reactive with oxygen such as transition metals selectedfrom the first, second or third transition series of the periodic tableof the elements, and include manganese II or III, iron II or III, cobaltII or III, nickel II or III, copper I or II, rhodium II, III or IV, andruthenium, for example disposed within a polymer matrix that can becoated onto or incorporated into a container. The transition metal is,for example, iron, nickel or copper. Other examples of oxygen scavengingelement may be enzymes which consumes, depletes or reduces the amount ofoxygen from the given environment without negatively affecting thepharmaceutical formula.

In one embodiment, the pharmaceutical formulation according to thepresent disclosure comprises a 100 mL aqueous solution packaged in thepolymer bag. In another embodiment, the pharmaceutical formulationaccording to the present disclosure comprises a 250 mL aqueous solutionpackaged in the polymer bag. In another embodiment, the pharmaceuticalformulation according to the present disclosure comprises a 500 mLaqueous solution packaged in the polymer bag. In another embodiment, thepharmaceutical formulation according to the present disclosure comprisesa 1000 mL aqueous solution packaged in the polymer bag.

In one embodiment, the gabapentin or the derivative ofgamma-aminobutyric acid comprises a minimum of about 100 mg to about2000 mg per container, for example about 500 mg to about 1000 mg, orfrom about 500mg to 1500 mg. In one embodiment, the container optionallyincludes at least one non-opioid pain drug comprising a minimum of about100 mg to about 2000 mg per container, for example about 500 mg to about1000 mg, or about 500mg to about 1500 mg.

In one embodiment, the concentration of the gabapentin or the derivativeof gamma-aminobutyric acid is less than about 99% (w/v) and theconcentration of the optional non-opioid pain drug concentration is lessthan about 99% (w/v). The concentration of the gabapentin or thederivative of gamma-aminobutyric acid can be about 1 to 200 mg/mL andthe concentration of the optional non-opioid pain drug can be about 1 to200 mg/mL. In another embodiment, the concentration of the gabapentin orthe derivative of gamma-aminobutyric acid can be about 1 to 400 mg/mLand the concentration of the optional non-opioid pain drug can be about1 to 400 mg/mL.

In one embodiment, the single dose of the pharmaceutical formulationdescribed herein comprises gabapentin, or a derivative ofgamma-aminobutyric acid, in the amount of 100-1200 mg, 400-1000 mg, 400mg, or 800 mg. In an embodiment, the single dose of the pharmaceuticalformulation described herein comprises gabapentin, or a derivative ofgamma-aminobutyric acid, in the amount of 100-1200 mg, 400-1000 mg, 400mg, or 800 mg, optionally combined with a non-opioid pain drug in theamount of in the amount of 100-2000 mg, 400-1600 mg, 800 mg, or 1000 mg.In an embodiment, the single dose of the pharmaceutical formulationdescribed herein comprises gabapentin, in the amount of 100-1200 mg,400-1000 mg, 400 mg, or 800 mg combined with a non-opioid pain drug inthe amount of in the amount of 100-2000 mg, 400-1600 mg, 800 mg, or 1000mg, wherein the non-opioid drug comprises acetaminophen.

In one embodiment, the pharmaceutical formulations of the presentdisclosure are sterilized by any means of sterilization suitable forpurposes of injectable infusion, including, for example (withoutlimitation), filtration through 0.22 micron filters, steamsterilization, radiation (e.g., gamma, electron beam, microwave), orethylene oxide sterilization.

In one embodiment, an injectable infusion comprising the pharmaceuticalformulations according to the present disclosure can have desirableproperties, including, for example (without limitation) desirablestability properties, pharmacokinetic properties, and bioavailability.One skilled in the art can readily determine the stability properties ofthe present formulations, for example by employing standard testingprocedures. For example, stability samples can be assayed for lactam andgabapentin by an HPLC procedure as set forth in Pharmaceutical Research,Vol. 9, No. 5, 1992, Stability Studies of Gabapentin in AqueousSolutions by E. Zour, et al., the entire disclosure of which is hereinincorporated by reference. In this procedure, the HPLC system uses adiode array detector. The samples are assayed on a reversed-phase B C18Ultrashpere ODS 5-μm, 4.6 mm×25-cm, column. The mobile phase comprisesof a water-methanol-acetonitrile (55:35:10) mixture and the flow ratecan be 1.0 ml/min. The detection is carried out at 210 nm. All samplesassayed are diluted 10-fold and then 50 μl of the sample is injectedinto the HPLC system. In one embodiment, HPLC retention times ofgabapentin and lactam are found to be about 3.1 and about 13.3 min.Initial studies indicated that at neutral pH, gabapentin or derivativesof gamma-am inobutyric acid have an aqueous shelf life of about 2 toabout 6 months at room temperature (25° C.), with a lactam limit ofabout 0.5%. Formulations of the present invention have a shelf-life ofabout 4-24 months at room temperature, for example about 18 to 24months, and this can be longer, and lactam limits of about 0.5% and thiscan be less.

In another example, high-performance liquid chromatography (HPLC) methodcan been used for the simultaneous determination of the main impuritiesof the non-opioid pain drug. For example, HPLC can be used forsimultaneous determination of the main impurities of acetaminophen,including for example n-propionyl-p-aminophenol,3-chloro-4-hydroxyacetanilide, 4′-hydroxyacetophenone,4-hydroxyacetophenone oxime, 4-acetoxyacetanilide and4′-chloroacetanilid, as set forth in Journal of Chromatographic Science,Vol. 50:335-342, 2012, HPLC Separation of Acetaminophen and itsImpurities Using a Mixed-mode Reversed-Phase/Cation Exchange StationaryPhase, by O. Calinescu, et al., the entire disclosure of which is hereinincorporated by reference. The chromatographic separation can beachieved on an Eclipse XDB-18 reversed-phase column using a gradientelution, with solvent A: 0.01 M phosphate buffer at pH 3.0 and solventB: methanol. Levels of these impurities in the present formulations arewell within acceptable limits, as are known in the art.

In one embodiment, parenteral administration of the pharmaceuticalformulation achieves a bioavailability of the gabapentin or thederivative of gamma-aminobutyric acid of about 20% to about 100% andelimination half-life of the gabapentin or the derivative ofgamma-aminobutyric acid is about 4 to about 8 hours. In one embodiment,parenteral administration of the pharmaceutical formulation achieves abioavailability of gabapentin or the derivative of gamma-am inobutyricacid that is higher than a bioavailability achieved by oraladministration. In one embodiment, parenteral administration of thepharmaceutical formulation achieves an elimination half-life ofgabapentin or the derivative of gamma-aminobutyric acid that is longerthan elimination half-life achieved by oral administration.

In one embodiment, methods of manufacturing a therapeutically effectiveinjectable pharmaceutical formulation are provided. The methods cancomprise dissolving gabapentin or a derivative of gamma-aminobutyricacid optionally combined with at least one non-opioid pain drug in anaqueous carrier, and adjusting a pH of the pharmaceutical formulation toabout 4.0 to about 8.0. The formulation can comprise one or moreformulations as described above.

In one embodiment, methods of stabilizing a therapeutically effectiveinjectable pharmaceutical formulation are provided. The methods cancomprise dissolving gabapentin or a derivative of gamma-aminobutyricacid optionally combined with at least one non-opioid pain drug in anaqueous carrier, dissolving a buffer in the aqueous carrier, andadjusting a pH of the pharmaceutical formulation to about 4.0 to about8.0 using the buffer. The formulation can comprise one or moreformulations as described above. Stability of the formulations can bedetermined by any suitable means known in the art, for example thosemethods described above.

In one embodiment, kits comprising at least one dosage form comprisingan injectable pharmaceutical formulation and instructions foradministering the at least one dosage form are provided. The formulationcan comprise one or more formulations as described above. Thetherapeutic instructions can comprise the step of intravascularlyadministering to a subject who has pain the pharmaceutical formulation.

In one embodiment, uses of gabapentin or a derivative ofgamma-aminobutyric acid optionally combined with at least one non-opioidpain drug for preparation of a medicament to treat post-procedural pain,wherein the medicament is administered by a dosing regimen, areprovided. The dosing regimen can comprise intravascularly, for exampleintravenously, administering to a subject who has pain an injectablepharmaceutical formulation. The formulation can comprise one or moreformulations as described above.

The dosage of the present formulations provided to a subject will varydepending upon the active ingredients being administered, the purpose ofthe administration, such as prophylaxis or therapy, and the state of thesubject and/or level of pain, the manner of administration, and thelike. In therapeutic applications, formulations described herein areprovided to a subject already suffering from pain, in an amountsufficient to at least partially ameliorate the symptoms of the painand/or its complications, including, for example (without limitation)post-procedural pain. An amount of present formulations comprising anactive ingredient adequate to accomplish this is defined as a“therapeutically effective amount.” The dosage to be used in thetreatment of a specific case must be subjectively determined by andwould be apparent to the ordinarily skilled physician or medicalprofessional. The variables involved for determining a therapeuticallyeffective amount of the present formulations include the specificcondition and the size, age, weight, gender, disease penetration, typeof procedure, and response pattern of the subject. The compounds can beadministered intravascularly, for example intravenously. The presentformulations can be provided as a unit dose, for example as an infusion,which taken together comprise a therapeutically effective amount. Forexample, a unit dose comprising a formulation of the invention can beadministered once daily or multiple times daily, for example 1, 2, 3, 4,5 or 6 times in a 12 or 24-hour period. If multiple unit doses areadministered in a given time period, they can be administered atsubstantially even time intervals. For example, if two unit doses areadministered in a 12-hour period, they can be given to the subject 6hours apart. Multiple unit doses are administered in a given time periodcan also be administered at substantially uneven time intervals. In oneembodiment, a unit dosage form comprises a formulation of the inventionin the form of an injectable infusion for intravenous administration.

The usual daily (i.e., 24-hour time period) dose depends on the specificcompound, method of treatment and condition treated. The usual dailydose for the gabapentin or derivative of gamma-aminobutyric acid isabout 1 to 500 mg/mL for parenteral application, for example 8 mg/mL,and for the at least one non-opioid pain drug is about 1 to 500 mg/mLfor parenteral application, for example 10 mg/mL.

In an embodiment, a pharmaceutical formulation of the present disclosurecomprises gabapentin, acetaminophen; in an aqueous carrier, wherein thepharmaceutical formulation has a pH of about 5.0 to about 7.0, andwherein a concentration of the gabapentin is about 5 to 15 mg/mL and aconcentration of the acetaminophen is about 5 to 15 mg/mL wherein such aformulation is suitable for intravenous administration and wherein sucha formulation is useful for the treatment of pain.

The following examples are given to illustrate exemplary embodiments ofthe present disclosure. It should be understood, however, that thepresent disclosure is not to be limited to the specific conditions ordetails described in these examples.

EXAMPLES

-   -   In the following Examples, “GBP” is used to mean gabapentin, and        “APAP” is used to mean acetaminophen

Example 1 Composition of Gabapentin (GBP) Formulation in Water ForInjection and Buffered Vehicles

Required quantities of Water for injection (WFI) were combined withCitrate Phosphate Buffer (10 mM), and Acetate Buffer (10 mM) in threeseparate manufacturing tanks. Gabapentin (GBP) was added to each oftanks to obtain a concentration of 10 mg/ml, and the pH was readjustedto 5.5 using HCl or NaOH. The bulk solution tanks were filled into 10 mLglass vials with a target fill volume of 10 mL and then stoppered andsealed. Samples were tested for assay and impurities. Samples were steamsterilized at 121° C. for 15 min and were analyzed for assay andimpurity levels.

TABLE 1 Gabapentin Formulations Example A Example B Example CIngredients Water for Citrate Acetate injection Phosphate Buffer (WFI)Buffer (10 mM) (10 mM) Amount /mL (mg) Gabapentin 10 Sodium Hydroxideq.s. Hydrochloric Acid q.s. Vehicle q.s. 1 mL pH 5.5 GBP Lactam GBPLactam GBP Lactam Assay (T0) (%) 102.0 ND 102.3 ND 101.7 ND PostSterilization 97.4 3.30 96.8 3.85 95.6 4.08 (%)Data in Table 1 demonstrates that unbuffered gabapentin (10 mg/mL) at pHof about 5.5 had significantly higher assay and lower level of impuritycompared to gabapentin in presence of citrate and acetate buffer.

Example 2 Composition of Gabapentin (GBP) Formulation in Presence ofDifferent Stabilizers and Solvents

GBP containing formulations were prepared by dissolving GBP to aconcentration of 9 mg/mL in acetate buffer. Additional stabilizers andsolvents were added as indicated in Table 2 below. A first set ofsamples were tested for assay and impurities after the initialpreparation of formulation, Another set of samples were steam sterilizedat 121° C. for 15 min and were tested for assay and impurity levels.

As shown in Table 2 (FIG. 1), GBP was found to be more stable insolutions containing polyvinyl pyrrolidone (PVP) at a concentration of10 mg/mL. Table 2 also depicts the stability of GBP in other solventsand stabilizers in the following order: PVP>Glycine>Lysine>PropyleneGlycol>Sorbitol>PEG400>Glycerol>Mannitol>SodiumOleate>β-cyclodextrin>Deoxychloic Acid>CMC>L-Glutamic Acid.

Example 3 Stability of GBP, APAP and APAP+GBP Formulation at pH 5.5

Formulation compositions were prepared by dissolving GBP and/or APAP asindicated in Table 3 and 4 and the pH was adjusted to 5.5 using HCl orNaOH.

TABLE 3 Stability of APAP, GBP and APAP + GBP formulations in water forinjection at pH 5.5 Q R S Ingredients Water for injection (WFI)Amount/mL Amount/mL Amount/mL (mg) (mg) (mg) Gabapentin 9 9Acetaminophen 10 10 Sodium Hydroxide q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5Hydrochloric Acid q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 Vehicle q.s. 1 mLq.s. 1 mL q.s. 1 mL GBP Lactam APAP GBP Lactam APAP Assay (T0) (%) 99.1ND 100.2 102.3 ND 101.2 Assay 2 Month 97.6 ND 100.4 99.1 ND 101.3 (%)

TABLE 4 Stability of APAP, GBP and APAP + GBP formulations in acetatebuffer at pH 5.5 T U V Ingredients Acetate Buffer (10 mM) Amount/mLAmount /mL Amount /mL (mg) (mg) (mg) Gabapentin 9 9 Acetaminophen 10 10Sodium Hydroxide q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 Hydrochloric Acidq.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 Vehicle q.s. 1 mL q.s. 1 mL q.s. 1mL GBP Lactam APAP GBP Lactam APAP Assay (T0) (%) 100.6 ND 101.6 101.8ND 101.8 Assay 2 Month (%) 98.0 ND 101.0 96.6 ND 100.7

As can be seen from Tables 3 and 4 above, all the three formulationswere stable for up to 2 months at 25° C. No significant difference instability of formulations were observed in formulations prepared inwater for injection or acetate buffer. Generation of lactam impurity wasnot observed in either of the formulation sets prepared with water forinjection or acetate buffer.

Example 4 Pharmacokinetics and Toxicologic Profile in Rats forAcetaminophen, Gabapentin Alone or in Combination

Formulation compositions were prepared by dissolving GBP and/or APAP asindicated in Table 5 and the pH was adjusted to 5.5 using HCl or NaOH.As observed in the previous study acetate buffer does not play any rolein stabilizing the formulation, therefore the formulation compositionsmentioned in Table 5 were prepared without use of acetate buffer.

Male rats were administered Acetaminophen (10 mg/mL) or Gabapentin (8mg/mL) alone or in combination with a vehicle control to evaluate thepharmacokinetic and toxicologic profile over a 24 h period following a15 minute IV infusion. Blood samples were collected over a 24 h periodat which time the rats were exsanguinated and blood collected forClinical Pathology (Chemistry, Hematology and Coagulation) evaluation.Finally, all animals were necropsied (all exterior and interior cavitiesand organs were examined) and the site of infusion in the jugular vein,lung, liver and kidney underwent histopathologic evaluation.

TABLE 5 Composition of APAP, GBP and APAP + GBP formulations employedfor in vivo studies. W X Y Water for injection (WFI) Amount/mL Amount/mLAmount/mL Ingredients (mg) (mg) (mg) Gabapentin 8 8 Acetaminophen 10 10Sodium Hydroxide q.s. q.s. q.s. Hydrochloric Acid q.s. q.s. q.s. Vehicleq.s. 1 mL q.s. 1 mL q.s. 1 mL pH 5.5 5.5 5.5

TABLE 6 Pharmacokinetic (PK) parameters observed after 15 min infusionof APAP, GBP and APAP + GBP formulations in rats. BioequivalentAcetaminophen PK Gabapentin PK Range (80-125%) C_(max) AUC C_(max) AUCC_(max) AUC Group (ng/mL) (ng · h/mL) (ng/mL) (ng · h/mL) (ng/mL) (ng ·h/mL) Saline 0 0 0 0 Acetaminophen 10,135 7,285  8,108-12,669 5,828-9,106  Gabapentin 20,138 37,663 APAP + GBP 13,550 8,526 20,02942,701 16,110-25 172 30,130-47,079

Results from this study demonstrate that treatment of rats with eitheracetaminophen or gabapentin alone or in combination in this formulationdid not alter the Clinical Pathology (Clinical Chemistry, Hematology orCoagulation Parameters) for these animals. Further there were no changesin the histopathology in any tissue sampled compared to the vehiclecontrol.

PK parameters were analyzed after 15 min infusion of APAP, GBP andAPAP+GBP formulations in rats. Maximal plasma concentration ofacetaminophen (C_(max)) obtained for APAP+GBP combination formulationwas found to be 30% higher when compared with C_(max) obtained afteradministering APAP alone. Whereas no change was observed in PK profileof GBP in the presence of APAP. The combination of APAP and GBP did notalter the total exposure (AUC, Area Under the Curve) compared to eitherdrug given alone.

Results from this study demonstrate that under the conditions of thisstudy this new formulation of APAP+GBP does not induce hemolysis of ratblood, alter clinical pathology parameters, nor induce changes in keytissues in the rats (infusion site, lung, liver, kidney and brain).

Example 5 Solubility Studies of APAP, GBP and APAP+GBP at Different pH(pH Range 4.0-8.0)

Solubility samples were prepared by dissolving APAP in water at 50 mg/mLconcentration and adjusting the pH in the required range. As can be seenfrom Table 7 no significant difference in solubility of APAP wasobserved in the overall pH range from 4.0-8.0.

TABLE 7 pH dependent solubility studies of APAP + GBP at different pHrange (4.0-8.0) Sample Acetaminophen(mg/mL) pH 4.0 13.8 pH 4.5 14.1 pH5.0 13.9 pH 5.5 13.9 pH 6.0 13.8 pH 6.5 13.9 pH 7.0 13.9 pH 7.5 13.9 pH8.0 14.2

TABLE 8 pH dependent solubility studies of GBP at different pH range(4.0-8.0) Sample Gabapentin (mg/mL) pH 4.0 129.2 pH 4.5 125.8 pH 5.0106.1 pH 5.5 101.3 pH 6.0 99.5 pH 6.5 97.5 pH 7.0 99.0 pH 7.5 98.6 pH8.0 98.7

Saturation solubility samples were prepared by addition of 150 mg/mL ofGBP in water and adjusting the pH in the required range. As can be seenfrom Table 8 solubility of GBP was higher at lower pH range (4.0-5.0)and was found to 98 mg/ml at the pH range of 6.0-8.0.

TABLE 9 pH dependent solubility studies of APAP + GBP at different pHrange (4.0-8.0) Sample Acetaminophen (mg/mL) Gabapentin (mg/mL) pH 4.032.9 125.7 pH 4.5 31.7 129.8 pH 5.0 30.7 126.7 pH 5.5 30.2 124.1 pH 6.028.8 120.0 pH 6.5 28.4 117.4 pH 7.0 30.5 122.3 pH 7.5 27.8 122.9 pH 8.031.3 123.0

Solubility samples were prepared by dissolving APAP and GBP in water at50 and 150 mg/mL concentration, respectively and adjusting the pH in therequired range. As can be seen from Table 9, solubility of APAPsolubility was increased to ˜30 mg/mL in presence of GBP which is morethan twice the solubility values obtained all the same pH range for APAPalone (Table 7).

Also significant increase in the solubility of GBP in presence of APAPwas also observed at pH range of 5.0-8.0 in comparison to solubilityvalues obtained in the same pH range for GBP alone (Table 8).

Example 6 Stability of APAP+GBP Formulation at Different pH (pH Range4.0-8.0)

Formulation compositions were prepared by dissolving APAP and GBP inwater at 10 and 8 mg/mL concentration, respectively and adjusting the pHin the required range.

As can be seen from Table 10 (FIG. 2), lactam impurity generated in 1month stability samples were well below the specifications (<0.5%) at pH5.5-7.0 (40° C./75% RH). Also, lactam impurity was not detected in 1month stability samples at pH 5.5-7.5 (40° C./75% RH). It is known thatAPAP undergoes hydrolytic degradation to form para-aminophenol. Themechanism involving hydrolysis was proposed by Koshy K. T. et al (JPharm Sci. 1961 Feb.; 50:113-8). Koshy et al has reported that thehydrolysis of APAP is minimum in the pH range 5 to 7 and it is desirableto keep the pH of the medium between 5 and 6 to obtain maximum shelflife for the APAP product. As reported in Table 10, APAP assay valuesobtained at pH 5.0-6.0 were 100% and low lactam impurity levels (<0.5%)were obtained for GBP around the same pH range (5.0-6.0). Hence, the pHof 5.5 was selected for APAP+GBP formulation prepared for futurestudies.

Example 7 In Vitro Hernolysis of Formulation of Acetaminophen,Gabapentin Alone or in Combination

APAP and GBP alone or in combination were evaluated in the in vitrohemolysis test using four biologic matrices (mouse, rat, dog and humanwhole unclotted blood) to determine the hemolytic potential for each onred blood cells. Blood was mixed with either Acetaminophen (2.5, 5, 10mg/mL), Gabapentin (2, 4, 8 mg/kg) or the combination, along with asaline control and positive control (2% SDS) and incubated for 15 min at37° C.

TABLE 11 Detection of hemolysis in mouse whole blood (male), rat wholeblood (male), beagle dog whole blood (male), human (pooled) whole bloodGBP GBP GBP (2 mg/mL) (4 mg/mL) (8 mg/mL) Species % Hemolysis MouseBlood 0 0 0 Rat Blood 0 0 0 Dog Blood 0 0 0 Human Blood 0 2 0 APAP APAPAPAP (2.5 mg/mL) (5 mg/mL) (10 mg/mL) Species % Hemolysis Mouse Blood 34 4 Rat Blood 2 0 0 Dog Blood 0 0 5 Human Blood 0 0 0 APAP APAP APAP (10mg/mL) + (10 mg/mL) + (10 mg/mL) + GBP GBP GBP (2 mg/mL) (4 mg/mL) (8mg/mL) Species % Hemolysis Mouse Blood 0 2 0 Rat Blood 0 0 2 Dog Blood 20 1 Human Blood 4 2 0

TABLE 12 Criteria for Determination of Hemolysis Percent HemolysisInterpretation <10% Not Hemolytic 10%-25% Relative Boundary (PossiblyHemolytic) >25% Hemolytic

Based on the results of this study (Table 11 and 12), in the currentformulation and concentrations tested, APAP and GBP alone or incombination were not considered to be hemolytic to Red Blood Cells underthe conditions tested (15 min at 37° C.) in mouse, rat, dog or humanwhole unclotted blood.

Example 8 Pharmacodynamic Parameters in Mice for Acetaminophen,Gabapentin Alone or in Combination

Two pharmacodynamic parameters were evaluated in the mouse model toevaluate the effects of Acetaminophen (1000 mg/dose), Gabapentin (800mg/dose) and the combination. Mouse tail flick test was conducted toevaluate test somatic pain and mouse rotorod/acelorod test evaluatedbehavioral changes, specifically somnolence or dizziness

A negative control (vehicle) and the test agents (Acetaminophen,Gabapentin or the combination) were administered by an IV route 30minutes before the initiation of testing. In each case a positivecontrol was administered as described below.

A. Tail-Flick Test:

The test evaluates somatic pain by measuring the time (seconds) requiredto elicit a tail flick response induced by focused radiant heat. A15-sec cut-off is used to prevent tissue damage. The study evaluatedbaseline measurements (before dosing) and at 30 minutes before theinitiation of the study (time 0) the mice were administered a 15-minuteIV infusion of either the Vehicle, Acetaminophen (10 mg/mL), Gabapentin(8 mg/mL) or the combination at a dose of 1.7 mL/kg. The positivecontrol, Morphine (0.6 mg/kg, 5 mg/kg by the IP route) 30 minutes priorto the initiation of the study. The measurements were conducted at 1, 2,4, and 6 hours after the initiation of the study FIG. 1. One-way ANOVAfollowed by Dunnett's test is applied for comparison between vehiclecontrol and test article treated groups. P<0.05 is consideredsignificant.

Results from this study indicate that the combination of Acetaminophenand gabapentin in the current formulation are superior to eithercompound alone under the conditions of this study.

As shown in FIG. 3, Mice were administered either Vehicle, Acetaminophen(10 mg/mL), Gabapentin (8 mg/mL) or a combination of the two test agentsby a 15 minute IV infusion 30 minutes before the start of the study. Abaseline was measured before administration of the test agents and at 1,2, 4 and 6 h post the start of the study. The effect of the compoundswas evaluated in the standard Tail-Flick test.

(B) RotoRod/Acelerorod Test:

Male ICR mice were trained on a RotoRod/Acelerod at a continuousaccelerating speed from 4 to 30 rpm/min during a time period of 4minutes for at least 3 times on day 0. Vehicle or test article at asingle dose is administered by intravenous infusion over 15 minutesstarting 30 minutes before the test period starts and chlorpromazine (30mg/kg, PO) was administered by oral gavage 60 minutes before the startof the test period. At 1, 2, 4, and 6 hours after the start of the testthe mice are placed on the accelerating rotorod (increasing from 4 to 30rpm/min during a 4 min period) and the time (seconds) the mouse remainedon the rotorod was recorded. One-way ANOVA followed by Dunnett's test isapplied for comparison between vehicle control and test article groups.P<0.05 is considered significant.

Results from this study indicate that at a dose of 10 mgAcetaminophen/mL, or 8 mg Gabapentin/mL or in combination, there was nostatistically significant decrease in motor control compared to thevehicle control (see FIG. 4).

As shown in FIG. 4, Mice were administered either Vehicle, Acetaminophen(10 mg/mL), Gabapentin (8 mg/mL) or a combination of the two test agentsby a 15 minute IV infusion 30 minutes before the start of the study. Abaseline was measured before administration of the test agents and at 1,2, 4 and 6 h post the start of the study. The effect of the compoundswas evaluated in the standard RotoRod/Acelerorod test.

Table 5 below provides a list of exemplary non-opioid pain drugs for usein pharmaceutical formulations according to the present disclosure,including exemplary daily dosage in mg. These non-opioid pain drugs inthe following total amounts can be substituted into the formulations ofExamples above.

TABLE 5 Exemplary non-opioid pain drugs NSAID Daily Dose Aspirin 250 mgIbuprofen 800 mg Naproxen 500 mg Indomethacin 15 mg Ketorolac 120 mgDiclofenac 150 mg Meloxicam 15 mg Celecoxib 200 mg Mefenamic acid 500 mgAcetaminophen 4000 mg

While the present disclosure has been discussed in terms of certainembodiments, it should be appreciated that the present disclosure is notso limited. The embodiments are explained herein by way of example, andthere are numerous modifications, variations and other embodiments thatmay be employed that would still be within the scope of the presentdisclosure.

1-32. (canceled)
 33. A method of treating pain in a subject in needthereof, comprising administering to the subject a pharmaceuticalformulation, the pharmaceutical formulation comprising, in a unit dosageform: a) a therapeutically-effective amount of pregabalin; b) atherapeutically-effective amount of acetaminophen; and c) an aqueouscarrier, wherein the pharmaceutical formulation has a pH of about 2 toabout
 10. 34. The method of claim 33, wherein the pharmaceuticalformulation has a pH of about 5 to about
 6. 35. The method of claim 34,wherein the pharmaceutical formulation has a pH of about 5.5.
 36. Themethod of claim 33, wherein the administration is intravenousadministration.
 37. The method of claim 33, wherein the administrationis parenteral administration.
 38. The method of claim 33, wherein thepregabalin is present in the pharmaceutical formulation at aconcentration of about 1 mg/mL to about 400 mg/mL.
 39. The method ofclaim 33, wherein the acetaminophen is present in the pharmaceuticalformulation at a concentration of about 1 mg/mL to about 400 mg/mL. 40.The method of claim 33, wherein the pregabalin is present in thepharmaceutical formulation at a concentration of about 200 mg/mL. 41.The method of claim 33, wherein the acetaminophen is present in thepharmaceutical formulation at a concentration of about 10 mg/mL
 42. Themethod of claim 33, wherein the administering is once daily.
 43. Themethod of claim 33, wherein the administering is more than once per day.44. The method of claim 33, wherein the aqueous carrier is water. 45.The method of claim 33, wherein the pharmaceutical formulation furthercomprises a buffer.
 46. The method of claim 33, wherein thepharmaceutical formulation further comprises an isotonicity adjustingagent.
 48. The method of claim 46, wherein the isotonicity adjustingagent is sodium chloride.
 49. The method of claim 46, wherein theisotonicity adjusting agent is mannitol.